Anaplastic Astrocytoma and Glioblastoma Multiforme

Pathophysiology and Pathogenesis. Malignant tumors are thought to evolve from lower grade tumors, although they can evolve spontaneously, perhaps as the result of abnormalities of gene function. Alteration of one gene may lead to transformation to a low-grade glioma, and subsequent cell division leads to the accumulation of multiple genetic alterations that ultimately result in a tumor with the histological characteristics of a glioblastoma multiforme. Alternatively, a putative glioblastoma multiforme gene may be affected immediately, resulting in a high-grade malignancy. A low-grade astrocytoma that is first diagnosed in a young patient may, many years later, recur as an anaplastic astrocytoma, and then subsequently as a glioblastoma multiforme. In another situation, a glioblastoma may occur in a patient with only a short history of neurological symptoms and a radiographically small tumor.

In recent years, multiple genetic alterations have been associated with malignant gliomas in different stages of malignant progression. These changes involve chromosomal changes in terms of deletion, addition, or duplication, or mutation or amplification of specific genes, as illustrated in I§b]e..4.6.-3 . The most frequently observed alterations include deletions in chromosomes 17p, 9p, and lOq as well as multiple copies of chromosome 7. Some changes are specific to certain types of tumor; for example, losses of genetic materials from chromosomes 1p, 9p, 10p, 10q, 11p, 13q, and 17p are often found in astrocytic tumors, whereas deletions in 19q are seen more often in oligodendrogliomas, and those of 22q occur in meningiomas. Mutations of the p53 gene are found in low-grade as well as high-grade gliomas, indicating that they may represent early events in the malignant transformation of normal astrocytes to astrocytic tumors. Alterations of the p16 and Rb (retinoblastoma) genes as well as the loss of chromosome 10 and amplification of the epidermal growth factor receptor (EGFR, ERBB) gene are found mostly in glioblastomas, suggesting that these changes are associated with late-stage tumor progression. Other, less frequently observed genetic abnormalities in malignant gliomas include overexpression of the platelet-derived growth factor (PDGF), transforming growth factor (TGF)-alpha and -beta, basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), insulin-like growth factors I and II, and the MYC, GLI, RES, FOS, and ROS oncogenes.^

The p53 gene encodes a 53-kD protein that functions as a transcriptional factor and is mapped to the short arm of chromosome 17. The wide-type (WT) p53 protein has been shown to have tumor suppression activity, and mutation of the WT gene has resulted in loss of this tumor suppressive



Suppressor Genes

Growth Factors/Growth Factor Receptors


pl6 (MTS1)






Retinoblastoma (Rb)



Chromosome lOq and lOp



Chromosome lp, llp, l9q, 22q




FGF, Fibroblast growth factor; FGFR, fibroblast growth factor receptor; EGF, epidenmal growth factor; EGFR, epilermal gronwth factor receptor; PDGF, platelet-derived growth factor; PDGFR, platelet-derived growth factor receptor; TGF, transforming growth factor; IGF, insulin-like growth factors; VEGF, vascular endothelial growth factor function, thus increasing the transformation risk of the normal cells. Deletion of the short arm of chromosome 17 (17p13) on which the p53 gene resides has been observed in over 60 percent of malignant astrocytomas. Mutations of p53 are rare in low-grade astrocytomas but are equally common in anaplastic astrocytoma and glioblastomas, suggesting that this p53 mutation may represent an early event in the genesis of glioma. However, other studies have demonstrated a higher frequency of p53 mutations in glioblastomas than in anaplastic astrocytomas. The fact that p53 mutations are detectable in small numbers of cells in a group of low-grade astrocytomas and are more frequently seen in the recurrent high-grade astrocytomas may indicate that the histological progression of low-grade astrocytoma to high-grade anaplastic astrocytoma is associated with clonal expansion of the transformed astrocytes carrying the same p53 mutations. The p53 protein is also a nuclear protein involved in the regulation of cell cycle proliferation. It mediates its growth effect through two major mechanisms: (1) induction of apoptosis, and (2) transient cell cycle arrest at G1 by induction of the p21 WAF1 (Cip1) protein. Furthermore, p53 gene function is inhibited by the oncogene mdm-2. Thus amplification of the mdm-2 protein may result in an alternative pathway for apoptosis independent of p53.

Loss of or deletions associated with chromosome 10 have been observed in high-grade malignant astrocytomas examined by cytogenetic and molecular techniques. Loss of an entire copy of chromosome 10 occurs in 80 to 90 percent of glioblastomas, and approximately 40 percent of these tumors also show amplification of the EGFR gene. Such a high frequency of loss of genetic material involving an entire copy or a large segment of chromosome 10 strongly suggests the presence of one or more than one tumor suppressor gene (TSG) on chromosome 10. This conclusion is partially substantiated by experiments in which a copy of normal chromosome 10 was reinserted into a glioblastoma cell; the resulting hybrid cells showed reversal of the malignant phenotype in vitro and in vivo. The hybrid cells were not able to form colonies in soft agar nor tumors in nude mice.

Epidermal growth factor receptor (EGFR, ERBB), a 170-kd glycoprotein, is amplified and overexpressed in 40 to 60 percent of gliomas. About 40 percent of gliomas show increased autophosphorylation activity of EGFR. However, no apparent relationship between amplification of EGFR and tumor grading can be established except that amplification of EGFR occurs almost exclusively in

glioblastomas. Several structurally and functionally altered EGFRs have also been found in approximately 40 percent of gliomas that show amplification of the EGFR gene. One class of mutant EGFR resembles the ERBB oncoprotein and is unable to bind EGF, but its intrinsic tyrosine kinase activity is not fully activated. A second mutant has an 83-amino acid deletion in domain 4, high-affinity EGF binding, enhanced tyrosine kinase activity, and the ability to transduce EGF-mediated glioma cell proliferation. The third mutant, which is seen in about 30 percent of glioblastoma with amplified EGFR, has an in-frame deletion of 267 amino acids in domains 1 and 2 and exhibits low-affinity binding for EGF, which then activates the intrinsic kinase activity. This mutant has been shown to have transformation activity. The fourth mutant is a larger (190-kd) protein that has autoactivated tyrosine kinase activity.

The TGF-alpha gene, which encodes for the 6-kd TGF-alpha peptide, has increased expression in many glioblastomas and anaplastic astrocytomas. TGF-alpha protein can be detected in all tumor specimens tested, and the higher grade tumors show stronger staining with anti-TGF-alpha monoclonal antibodies. In several glioma cell lines, TGF-alpha is cell associated and is not secreted into the medium. Together with EGFR, TGF-alpha forms an autocrine growth mechanism. Moreover, TGF-alpha also has been shown to have angiogenesis activity that is capable of stimulating endothelial cell growth, thus forming small capillaries feeding the tumor.

Vascular endothelial growth factor (VEGF), a 34- to 43- kd dimeric glycoprotein, induces endothelial cell proliferation, angiogenesis, and capillary permeability. Three mRNA forms are produced by alternative splicing and code for three protein products, VEGF 189 , VEGF165 , and VEGF, 21 . VEGF, as opposed to EGF, is mitogenic specifically for tumor endothelial cells that display increased expression of VEGF receptors, suggesting that VEGF acts as the mediator for tumor angiogenesis. VEGF has also been shown to increase capillary permeability, suggesting that it may play an important role in tumor-induced edema. Because increased tumor vascularity and peritumoral edema are key features of high-grade astrocytomas, and because VEGF plays a unique role in angiogenesis and edema, it is especially important to understand VEGF's role in glioma transformation and progression.

Fibroblast growth factors (FGFs) are a family of heparin-binding proteins that express both mitogenic and angiogenic properties. Elevated levels of aFGF and bFGF are expressed in human glioma cells. More recently, elevated levels of bFGF and bFGF-receptor have been described in a human glioma cell line in which the influence of endogenously excreted bFGF on cellular proliferation is downregulated by antisense oligonucleotide primers. Immunostaining experiments have also demonstrated elevated levels of bFGF in glioma cells as well as endothelial cells in all glioma specimens tested.

The p16 gene, also known as the MTS1 gene, is localized to the 9p21 region. It is a potent inhibitor of the cyclin-dependent kinases 4 and 6 (cdk4 and cdk6) and is often mutated and deleted in a variety of human cancers including gliomas. The p16 protein functions by forming a complex with D1 cyclin and prevents D1 cyclin and cdk4 from forming a phosphoprotein complex, thus paralyzing the activation of the retinoblastoma (Rb) gene and resulting in a G1 blockade. A mutation or deletion of the p16 gene allows formation of an active Rb protein, thus allowing cells to proceed through the normal cell cycle and maintain continued proliferation.

Mutations of the Rb gene, a well-characterized tumor suppressor gene, have been reported in 20 to 30 percent of malignant gliomas. They usually are associated with glioblastomas, suggesting that alteration of the Rb gene represents a late event. Hypophosphorylated Rb protein is essential to allow cells to remain in G1 without entering mitosis and proceeding to the G2 to M phases. Mutation and deletion of the Rb gene renders this critical step inactive and allows cells to continue to go through proliferation.

Epidemiology and Risk Factors. Malignant astrocytomas, including anaplastic astrocytoma and glioblastoma multiforme, are seen more often in adults and are characterized by a shorter survival time than low-grade astrocytomas. They constitute over 50 percent of all malignant tumors diagnosed and are the third most frequent type of cancer in the 15- to 34-year-old age group and the fourth most frequent in the 35- to 54-year-old age group. Incidence increases with age, especially after 50 years, and a higher frequency of glioblastoma multiforme than anaplastic astrocytoma is seen in successive decades. Malignant astrocytomas arise primarily in the frontal lobes and cerebral hemispheres. Anaplastic astrocytomas are differentiated from astrocytomas by histological evidence of increasing cellular atypia and nuclear pleomorphism. The addition of necrosis labels the tumor as glioblastoma multiforme.

Clinical Features and Associated Disorders. Symptoms of these high-grade tumors can arise gradually, reflecting the manner of evolution of astrocytomas. More often, immediate symptoms are found, such as seizures (either focal or generalized), speech disturbances, a change in or increasingly severe headache, vomiting, nausea, visual disturbances, and weakness or sensory disturbances. Careful interviews with the patient or family members may lead to the unappreciated discovery of neurobehavioral symptoms. Elderly patients may have memory loss, suggesting dementia. Occasionally, older patients present with a sudden onset of focal neurological findings that are believed to be a vascular event. Neuroradiographic imaging abnormalities (often CT performed without contrast dye) are consistent with a vascular distribution, leading to a mistaken diagnosis of stroke. However, instead of improving, these patients often continue to deteriorate. Such patients should be re-evaluated with MRI performed with gadolinium. Malignant gliomas are considered to have no definite hereditary association. There are case reports of family members who have had similar tumors in an autosomal dominant fashion, and studies have found a familial association in 7 percent of cases. y Turcot's syndrome is a genetic disease in which gastrointestinal adenomatous polyps and primary brain tumors, including gliomas and medulloblastoma, are combined. It is dominantly inherited and has been associated with the gene for familial adenomatous polyposis and should be considered a variant. Gliomas are also associated with neurofibromatosis (see subsequent discussion) and tuberous sclerosis.

Differential Diagnosis. Patients with malignant astrocytomas have a differential diagnosis similar to that listed

for astrocytomas. Practitioners must be aware that a definitive diagnosis cannot be made on the basis of the neuroradiological evaluation alone. It is essential to obtain tissue diagnosis by surgical resection or biopsy when feasible. The main differential is between an abscess and a malignant tumor (either a primary brain tumor, lymphoma, or metastasis). Because of the increasing number of multifocal gliomas, the presence of multiple lesions does not always indicate metastatic disease from a systemic cancer.

Evaluation. Patients often present with a single lesion. Physicians may be tempted to undertake an extensive search for a primary cancer elsewhere that is often unfruitful, ultimately requiring resection of the lesion. Patients with large lesions that are amenable to resection should undergo a complete neurological and physical examination with rectal examination and stool guaiac analysis (including a pelvic examination in women and a testicular examination in men), complete blood count, serum chemistries, coagulation profile, chest x-ray, and MRI of the brain with high-dose gadolinium ( Fig:...,46z4 ). If no other lesions are seen, biopsy and surgical resection are indicated to determine the pathological diagnosis. Even if the tumor is found to be metastatic, resection of a single metastasis has been shown to prolong survival.y

Comprehensive neurobehavioral studies can be performed prior to surgery to determine pretreatment deficits. After surgery, re-evaluation may be indicated to define areas of improvement and provide a baseline before further therapy is undertaken. These studies can help patients and their families define those areas that may be a problem for the patient. Such studies can help as the patient begins to adjust to daily living at home, and they can also increase the ease of patient care. Recent data documenting the risk

Figure 46-4 MRI picture of a glioblastoma multiforme demonstrating a large contrast-enhancing left temporal lesion with irregular border, as well as a central lucency suggesting an area of necrosis.

of cognitive impairment after surgery have not shown that significant worsening occurs. Indeed, in some patients, surgical debulking may improve cognitive status as well as other neurological symptoms and signs of disease.

Management. Patients are often treated with steroids, usually dexamethasone, immediately on discovery of a lesion in the brain. Unless the patient is in danger of herniation or has another serious problem that specifically requires steroids, such treatment is not indicated. Cases of primary CNS lymphoma in patients without acquired immune deficiency syndrome (AIDS) have increased in frequency (see later discussion). Dexamethasone can be oncolytic to some tumors, especially leukemias and lymphomas, leading to resolution of lesions and causing diagnostic confusion. Therefore, we favor delaying the use of steroids until after the tumor has been evaluated but before surgery. Dexamethasone is the steroid of choice because it is a glucocorticoid with no mineralocorticoid activity and has better CNS penetration than other steroid preparations. Occasionally, patients with large lesions may require dexamethasone for several days before surgery. After surgical debulking has been performed, steroids can be rapidly tapered. Radiation oncologists often maintain patients on low doses of dexamethasone throughout radiotherapy, usually 2 to 4 mg a day. H2 blockade is routinely given with steroids to prevent ulcers, although some believe the risk of ulceration is not sufficiently high to warrant its use. After radiotherapy is complete, steroids can usually be stopped by gradually tapering the dose.

All patients in whom the tumor has been diagnosed pathologically require surgical intervention. Recently, there has been an increase in the use of limited surgery with stereotactic biopsy. In patients in whom mass lesions can be safely removed, maximum surgery is indicated. Small biopsies may not provide sufficient tissue to allow accurate neuropathological interpretation, leading to incorrect therapeutic intervention. All patients should be offered treatment in clinical trials whenever possible. The advent of computer listings of available studies on the Internet may facilitate enrollment in these studies.

The use of anticonvulsant medications prophylactically in patients with newly discovered mass lesions remains controversial. There are no studies that allow a direct answer to the question of whether patients are at increased risk of seizures. This question is complicated by the fact that virtually all patients undergo surgical decompression or biopsy and are given anticonvulsants at that time. We do not routinely administer anticonvulsants until a patient has sustained a seizure. Certainly, any patient presenting with seizures should be so treated.

Cranial radiation following surgery remains the mainstay of treatment. Maximum radiation dose of 6000 to 6500 cGy is recommended. Recent radiotherapy techniques involve the application of approximately 4600 cGy to a larger field with a 2- to 3-cm margin encompassing the contrast-enhancing tumor, and an additional 2000 cGy delivered to a reduced field encompassing only the contrast-enhancing abnormality. Irradiation to the brain during pregnancy has been shown to be feasible with minimal risk to the fetus.y Brachytherapy, in which radioactive seeds are applied into the tumor area, has been shown to be beneficial in some patients with glioblastoma multiforme. Unfortunately, this

technique yields substantial morbidity; the high risk of radiation necrosis necessitates reoperation in approximately 50 percent of patients undergoing interstitial brachytherapy. It is useful only in a limited number of patients with polar tumors. Stereotactic radiation may increase survival in those patients with radiosensitive tumors'201 ; however, neither the neurobehavioral effects of this treatment or randomized studies have been reported. Effects of radiation include hypersomnolence during treatment and cognitive dysfunction. These effects are more commonly seen in patients with prolonged survival after radiotherapy.

Chemotherapy regimens continue to evolve and have produced improvement in the overall time of tumor progression and patient survival. The standard treatment includes the use of nitrosourea-based regimens such as carmustine (BCNU) alone or the triple drug regimen of lomustine (CCNU), procarbazine, and vincristine (PCV).y Salvage chemotherapy regimens with agents such as carboplatin, VP16, procarbazine, interferons, and diaziquone (AZQ) produce mixed results, but some responses occur. The efficacy of chemotherapy declines with patient age. y Blood-brain barrier disruption agents, carotid artery infusion, and combination therapy with multiple agents have not demonstrated overall benefit. An analysis of the changes in normal biological function or chromosomal aberrations occurring in tumor cells and their response to chemotherapy is under way. '231 , y

Prognosis and Future Perspectives. Overall, prognosis is related to histological diagnosis, age, performance status, and treatment. Patients who receive more complete surgical resection tend to survive longer. Follow-up resection after tumor regrowth also prolongs survival and increases overall well-being in many patients.

Median survival for patients with a glioblastoma multiforme, without accounting for age, is approximately 1 year. Patients with anaplastic astrocytoma have a life expectancy of 3 to 5 years. Prolonged survival with diagnosis of a malignant glioma can occur but may suggest incorrect pathological diagnosis of tissue type. In a review of patients entered in Radiation Therapy Oncology Group (RTOG) studies, histology was the most important determinant of survival for patients younger than 50 years of age, whereas performance status was the most important variable for patients over age 50. y

Clinical trials have to be conducted to better define the effects of treatment, including surgery, radiotherapy, and chemotherapy. Accrual of all brain tumor patients into clinical studies stands at 10 percent. Careful analysis and evaluation of all patients with these tumors is needed. Recent concerns have been raised about possible enrollment bias.y Newer imaging techniques must be developed to better evaluate both the disease and the treatment response. Positron emission tomography has not been demonstrated to separate reliably the tumor from the treatment effects. Recent phase I studies of gene therapy for these tumors have been initiated, and results have demonstrated infrequent short-term responses. The combination of gene therapy with other modalities, including concomitant chemotherapy, remains to be studied.

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